EP2391603B1 - Pipéridines substitués par aroylamino et hétéroaroylamino comme inhibiteurs de glyt-1 - Google Patents

Pipéridines substitués par aroylamino et hétéroaroylamino comme inhibiteurs de glyt-1 Download PDF

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EP2391603B1
EP2391603B1 EP10700563.9A EP10700563A EP2391603B1 EP 2391603 B1 EP2391603 B1 EP 2391603B1 EP 10700563 A EP10700563 A EP 10700563A EP 2391603 B1 EP2391603 B1 EP 2391603B1
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trifluoromethyl
phenyl
piperidin
methyl
benzamide
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EP2391603A1 (fr
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Sabine Kolczewski
Emmanuel Pinard
Henri Stalder
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F Hoffmann La Roche AG
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/56—Amides
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    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

  • the present invention relates to a compound of general formula I wherein
  • the present invention relates to pharmaceutical compositions containing the compounds of formula I and to their use in the treatment of neurological and neuropsychiatric disorders. It has surprisingly been found that the compounds of general formula I are good inhibitors of the glycine transporter 1 (GlyT-1), and that they have a good selectivity to glycine transporter 2 (GlyT-2) inhibitors.
  • GlyT-1 glycine transporter 1
  • GlyT-2 glycine transporter 2
  • WO 01/81308 A2 describes also piperidine derivatives which are suitable as GlyT1 inhibitors. But the very specific substitution pattern on the piperidine ring, such as the nature of the substituent R 1 as well as the nature and position of R and Ar-C(O)-NH- is well outside the scope of the compounds according to WO 01/81308 A2 .
  • Schizophrenia is a progressive and devastating neurological disease characterized by episodic positive symptoms such as delusions, hallucinations, thought disorders and psychosis and persistent negative symptoms such as flattened affect, impaired attention and social withdrawal, and cognitive impairments ( Lewis DA and Lieberman JA, Neuron, 2000, 28:325-33 ).
  • episodic positive symptoms such as delusions, hallucinations, thought disorders and psychosis
  • persistent negative symptoms such as flattened affect, impaired attention and social withdrawal, and cognitive impairments
  • PCP phencyclidine
  • ketamine non-competitive NMDA receptor antagonists
  • transgenic mice expressing reduced levels of the NMDAR1 subunit displays behavioral abnormalities similar to those observed in pharmacologically induced models of schizophrenia, supporting a model in which reduced NMDA receptor activity results in schizophrenia-like behavior ( Mohn AR et al., 1999, Cell, 98: 427-236 ).
  • Glutamate neurotransmission in particular NMDA receptor activity, plays a critical role in synaptic plasticity, learning and memory, such as the NMDA receptors appears to serve as a graded switch for gating the threshold of synaptic plasticity and memory formation ( Hebb DO, 1949, The organization of behavior, Wiley, NY ; Bliss TV and Collingridge GL, 1993, Nature, 361: 31-39 ).
  • Transgenic mice overexpressing the NMDA NR2B subunit exhibit enhanced synaptic plasticity and superior ability in learning and memory ( Tang JP et al., 1999, Nature: 401- 63-69 ).
  • the amino acid glycine is known to have at least two important functions in the CNS. It acts as an inhibitory amino acid, binding to strychnine sensitive glycine receptors, and it also influences excitatory activity, acting as an essential co-agonist with glutamate for N-methyl-D-aspartate (NMDA) receptor function. While glutamate is released in an activity-dependent manner from synaptic terminals, glycine is apparently present at a more constant level and seems to modulate/control the receptor for its response to glutamate.
  • NMDA N-methyl-D-aspartate
  • One of the most effective ways to control synaptic concentrations of neurotransmitter is to influence their re-uptake at the synapses.
  • Neurotransmitter transporters by removing neurotransmitters from the extracellular space, can control their extracellular lifetime and thereby modulate the magnitude of the synaptic transmission ( Gainetdinov RR et al, 2002, Trends in Pharm. Sci., 23(8): 367-373 ).
  • Glycine transporters which form part of the sodium and chloride family of neurotransmitter transporters, play an important role in the termination of post-synaptic glycinergic actions and maintenance of low extracellular glycine concentration by re-uptake of glycine into presynaptic nerve terminals and surrounding fine glial processes.
  • GlyT-1 and GlyT-2 Two distinct glycine transporter genes have been cloned (GlyT-1 and GlyT-2) from mammalian brain, which give rise to two transporters with ⁇ 50 % amino acid sequence homology.
  • GlyT-1 presents four isoforms arising from alternative splicing and alternative promoter usage (1a, 1b, 1c and 1d). Only two of these isoforms have been found in rodent brain (GlyT-1a and GlyT-1b).
  • GlyT-2 also presents some degree of heterogeneity.
  • Two GlyT-2 isoforms (2a and 2b) have been identified in rodent brains.
  • GlyT-1 is known to be located in CNS and in peripheral tissues, whereas GlyT-2 is specific to the CNS.
  • GlyT-1 has a predominantly glial distribution and is found not only in areas corresponding to strychnine sensitive glycine receptors but also outside these areas, where it has been postulated to be involved in modulation of NMDA receptor function ( Lopez-Corcuera B et al., 2001, Mol. Mem. Biol., 18: 13-20 ).
  • one strategy to enhance NMDA receptor activity is to elevate the glycine concentration in the local microenvironment of synaptic NMDA receptors by inhibition of GlyT-1 transporter ( Bergereon R. Et al., 1998, Proc. Natl. Acad. Sci. USA, 95: 15730-15734 ; Chen L et al., 2003, J. Neurophysiol., 89 (2): 691-703 ).
  • Glycine transporters inhibitors are suitable for the treatment of neuroligical and neuropsychiatric disorders.
  • the majority of diseases states implicated are psychoses, schizophrenia ( Armer RE and Miller DJ, 2001, Exp. Opin. Ther. Patents, 11 (4): 563-572 ), psychotic mood disorders such as severe major depressive disorder, mood disorders associated with psychotic disorders such as acute mania or depression associated with bipolar disorders and mood disorders associated with schizophrenia, ( Pralong ET et al., 2002, Prog. Neurobiol., 67: 173-202 ), autistic disorders ( Carlsson ML, 1998, J. Neural Transm.
  • cognitive disorders such as dementias, including age related dementia and senile dementia of the Alzheimer type, memory disorders in a mammal, including a human, attention deficit disorders and pain ( Armer RE and Miller DJ, 2001, Exp. Opin. Ther. Patents, 11 (4): 563-572 ).
  • NMDA receptors via GlyT-1 inhibition may lead to agents that treat psychosis, schizophrenia, dementia and other diseases in which cognitive processes are impaired, such as attention deficit disorders or Alzheimer's disease.
  • Objects of the present invention are the compounds of formula I per se, the use of compounds of formula I and their pharmaceutically acceptable salts for the manufacture of medicaments for the treatment of diseases related to activation of NMDA receptors via Glyt-1 inhibition, their manufacture, medicaments based on a compound in accordance with the invention and their production as well as the use of compounds of formula I in the control or prevention of illnesses such as psychoses, dysfunction in memory and learning, schizophrenia, dementia and other diseases in which cognitive processes are impaired, such as attention deficit disorders or Alzheimer's disease.
  • the preferred indications using the compounds of the present invention are schizophrenia, cognitive impairment and Alzheimer's disease.
  • the invention includes all racemic mixtures, all their corresponding enantiomers and/or optical isomers.
  • lower alkyl denotes a saturated straight- or branched-chain group containing from 1 to 7 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, 2-butyl, t-butyl and the like.
  • Preferred alkyl groups are groups with 1 - 4 carbon atoms.
  • lower alkoxy denotes a lower alkyl group as defined above, which is linked with an O atom.
  • cycloalkyl denotes a saturated or partially saturated ring containing from 3 to 7 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl or cycloheptenyl.
  • Preferred cycloalkyl rings are cyclopropyl and cyclopentyl.
  • heterocycloalkyl denotes a saturated or partially saturated ring containing from 3 to 6 carbon atoms, wherein at least one carbon atom is replaced by a heteroatom selected from N, S or O, for example piperazinyl, pyrrolidinyl, oxetanyl, morpholinyl piperidinyl, or tetrahydropyranyl.
  • halogen denotes chlorine, iodine, fluorine and bromine.
  • aryl denotes a monovalent cyclic aromatic hydrocarbon radical consisting of one or more fused rings in which at least one ring is aromatic in nature, for example phenyl or naphthyl.
  • lower alkyl substituted by halogen denotes a lower alkyl group as defined above, wherein at least one hydrogen atom is replaced by a halogen atom, for example the following groups: CF 3 , CHF 2 , CH 2 F, CH 2 CF 3 , CH 2 CHF 2 , CH 2 CH 2 F, CH 2 CH 2 CF 3 , CH 2 CH 2 CH 2 CF 3 , CH 2 CH 2 Cl, CH 2 CF 2 CF 3 , CH 2 CF 2 CHF 2 , CF 2 CHFCF 3 , C(CH 3 ) 2 CF 3 , CH(CH 3 )CF 3 or CH(CH 2 F)CH 2 F.
  • lower alkoxy substituted by halogen denotes an alkoxy group, wherein at least one hydrogen atom is replaced by halogen as defined above.
  • heteroaryl denotes a cyclic aromatic hydrocarbon radical consisting of one or more fused rings containing 5-14 ring atoms, preferably containing 5-10 ring atoms, in which at least one ring is aromatic in nature, and which contains at least one heteroatom, selected from N, O or S, for example quinoxalinyl, dihydroisoquinolinyl, pyrazinyl, pyridazinyl, pyrazolyl, pyridinyl, pyridyl, pyrimidinyl, oxadiazolyl, triazolyl, tetrazolyl, thiazolyl, thiadiazolyl, thienyl, furyl, imidazolyl, benzofuranyl, dihydrobenzofuranyl and benzo[1,3]dioxole.
  • Preferred heteroaryl group is pyridinyl.
  • pharmaceutically acceptable acid addition salts embraces salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, p-toluenesulfonic acid and the like.
  • Preferred compounds of formula I are those, wherein R 1 is lower alkyl and Ar and R are phenyl.
  • phenyl group for Ar is substituted by at least two CF 3 groups, for example the following compounds:
  • Preferred compounds of formula I are those, wherein R 1 is cycloalkyl or heterocycloalkyl and Ar and R are phenyl, for example
  • Preferred compounds of formula I are those, wherein R 1 is lower alkyl, Ar is phenyl and R is heteroaryl, for example
  • Preferred compounds of formula I are those, wherein R 1 is hydrogen and Ar and R are phenyl, for example. rac-2-cyclopropyl-N-(3-phenyl-piperidin-3-yl)-4-trifluoromethyl-benzamide.
  • Preferred compounds of formula I are those, wherein R 2 is hydroxy, for example rac-N-(5-hydroxy-1-methyl-3-phenyl-piperidin-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide or N-((3R,5S) or (3S,5R)-5-hydroxy-1-methyl-3-phenyl-piperidin-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide.
  • Preferred compounds of formula I are those, wherein R 2 is halogen, for example rac-N-(5-fluoro-1-methyl-3-phenyl-piperidin-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide.
  • Preferred compounds of formula I are those, wherein R 1 is CD 3 , for example the following compound [2H-methyl]-2-methoxy-N-(R) or (S)-1-methyl-3-phenyl-piperidin-3-yl)-6-methylsulfanyl-4-trifluoromethyl-benzamide hydrochloride.
  • the compounds of formula I may be prepared in accordance with process variant a) or b) or c) and with the following schemes 1- 12.
  • the starting material is commercially available or may be prepared in accordance with known methods.
  • Piperidine derivatives of formula II can be prepared by reacting piperidine derivatives of formula II with acid of formula III in the presence of an activating agent like HATU (o-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) or thionyl chloride.
  • Piperidine derivatives of formula II can be prepared by reacting piperidone derivative VI with an organometallic reagent like a Grignard to provide alcohol VII followed by a treatment with sodium azide in the presence of an acid like TFA to provide azide derivative VIII which is transformed into II in the presence of a reducing agent like lithium aluminium hydride.
  • piperidine derivatives of formula II in which R 2 is hydrogen can be prepared from nitro-piperidone derivatives XII after reduction of the nitro group with reducing agent like Raney Nickel under an atmosphere of hydrogen or like Zinc in the presence of acid like hydrochloride acid to provide amino-piperidone derivatives XIII which can be reduced to II in the presence of reducing agent like lithium aluminium hydride.
  • Nitro-piperidone derivatives XII can be prepared from nitro derivatives XI according to an intramolecular Mannich type reaction performed in the presence of an amine: R 1 NH 2 and an aldehyde like formaldehyde.
  • XI can be prepared by Michael addition of nitro-methyl-aryl derivatives IX onto methyl acrylate in the presence of base like Amberlyst A21 or Triton B or by reacting aryl halide derivatives X with methyl 4-nitrobutyrate in the presence of Palladium catalyst like Pd 2 dba 3 , ligand like 2-(di-t-butylphosphino)-2'-methybiphenyl and base like cesium carbonate as described by Buchwald et al. in J. Org. Chem. 2002, 106 .
  • piperidine derivatives of formula II in which R is an alkyl group can be prepared from acid XVI after a Curtius rearrangement in the presence of a reagent like DPPA (diphenylphosphoryl azide) to provide isocyanate XVII which is then hydrolyzed in presence of base like sodium hydroxide to lead to protected piperidine XVIII that is reduced in II in a presence of a reducing agent like lithium aluminiumhydride.
  • Acid XVI can be prepared from ester XIV after treatment with a base like lithium diisopropylamide and an alkylating agent R-X to provide intermediate ester XV which is then saponified to XVI in the presence of base like lithium hydroxide.
  • R 4 and R 5 are lower alkyl or form together with the carbon atom to which they are attached a cycloalkyl or heterocycloalkyl group.
  • compounds of general formula I can be prepared by reaction of piperidine derivative IV with either an alkylating agent R 1 X in the presence of base like N-ethyldiisopropylamine or with a carbonyl reagent V in the presence of a reducing agent like sodium cyanoborohydride.
  • Piperidine derivative IV can be prepared after reduction of azide VIII with reagent like sodium borohydride to provide amine derivative XIX which can be then coupled with acid III in the presence of an activating agent like HATU or thionyl chloride to yield amide derivative XX which is then transformed into IV after cleavage of the N-protective group.
  • piperidine derivatives of formula II in which R 2 is fluorine can be prepared from fluorinated nitro piperidone XXI after two consecutive reductions with first: using agent like Raney Nickel and second: using agent like lithium aluminiumhydride.
  • XXI can be prepared by reaction of nitro piperidine XII with a base like lithium diisopropylamine followed by treatment with an electrophilic fluorinating agent like N-fluorobenzenesulphonimide.
  • piperidine derivatives of formula II in which R 2 is alkyl can be prepared from alkylated nitro piperidone XXIII after two consecutive reductions with first: using agent like Raney Nickel and second: using agent like lithium aluminiumhydride.
  • XXIII can be prepared by reaction of nitro piperidine XII with a base like lithium diisopropylamine followed by treatment with an electrophilic alkylating agent like R 2 X where X is an halogen.
  • piperidine derivatives of formula II which contains two geminal alkyl group R 2 can be prepared from bis-alkylated nitro piperidone XXV after two consecutive reductions with first: using agent like Raney Nickel and second: using agent like lithium aluminiumhydride.
  • XXV can be prepared by reaction of mono-alkylated nitro piperidine XXIII with a base like lithium diisopropylamine in the presence of TMEDA (tetramethylethylenediamine) followed by treatment with an electrophilic alkylating agent like R 2 X where X is an halogen.
  • XXVIII can be prepared from XXVII by reaction with a base like sodium hydride and an electrophilic alkylating agent like R 6 X where X is an halogen.
  • XXVII can be prepared by reaction of nitro piperidine XII with a base like lithium diisopropylamine followed by treatment with an electrophilic hydroxylating agent like (oxodiperoxy(pyridine) (1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone)molybdenum(IV)) or bis(trimethylsilyl)peroxide.
  • a base like lithium diisopropylamine
  • an electrophilic hydroxylating agent like (oxodiperoxy(pyridine) (1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone)molybdenum(IV)) or bis(trimethylsilyl)peroxide.
  • piperidine derivatives of formula II in which R is an heteroaryl group like pyridine can be prepared from nitro piperidine thione XXX after two consecutive reductions, with first: using agent like sodium borohydride and second: using agent like Raney Nickel.
  • XXX can be prepared from nitro piperidinone XXII by reaction with Lawesson's reagent.
  • piperidine derivatives of formula II which contains two geminal methyl groups can be prepared from Boc-protected amino piperidinone XXXII after reaction with methylmagnesium bromide and Zirconium (IV) chloride followed by cleavage of the Boc group under acidic condition.
  • XXXII can be prepared after reaction of amino piperidone XIII with di-tert-butyl dicarbonate.
  • piperidine derivatives of formula II which contains a cyclopropyl unit can be prepared from Boc-protected amino piperidinone XXXII after reaction with ethyl magnesium bromide and titanium isopropoxide followed by cleavage of the Boc group under acidic condition.
  • piperidine derivatives of formula II in which R 2 is an alkyl group can be prepared from nitro derivative XXXIX following an intramolecular Mannich reaction performed in the presence of an aldehyde like formaldehyde to provide nitro piperidine XXXX which is then treated with a reducing agent like Raney Nickel.
  • XXXIX can be obtained by deprotection of Boc-protected nitro derivative XXXVIII which can be prepared by reaction of nitro derivative XXXI with halogenated compound XXXVII in the presence of a base like n-butyl lithium.
  • XXXVII can be obtained after protection and halogenation of amino alcohol XXXV.
  • Racemic mixtures of chiral compound I can be separated using chiral HPLC.
  • the acid addition salts of the basic compounds of formula I may be converted to the corresponding free bases by treatment with at least a stoichiometric equivalent of a suitable base such as sodium or potassium hydroxide, potassium carbonate, sodium bicarbonate, ammonia, and the like.
  • a suitable base such as sodium or potassium hydroxide, potassium carbonate, sodium bicarbonate, ammonia, and the like.
  • step 1 rac-3-Hydroxy-3-phenyl-piperidine-1-carboxylic acid benzyl ester
  • step 2 rac-3-Azido-3-phenyl-piperidine-1-carboxylic acid benzyl ester
  • step 3 rac-1-Methyl-3-phenyl-piperidin-3-ylamine
  • step1-3 the title compound was prepared from 3-oxo-piperidine-1-carboxylic acid benzyl ester (commercial) and 4-fluoro-phenylmagnesium bromide. MS(m/e): 209.2 (M+H + ).
  • step1-3 the title compound was prepared from 3-oxo-piperidine-1-carboxylic acid benzyl ester (commercial) and 4-chloro-phenylmagnesium bromide. MS(m/e): 225.3 (M+H) + .
  • step1-3 the title compound was prepared from 3-oxo-piperidine-1-carboxylic acid benzyl ester (commercial) and 4-methyl-phenylmagnesium bromide. MS(m/e): 205.3 (M+H + ).
  • step 1 3-Hydroxy-2-methyl-piperidine-1-carboxylic acid benzyl ester
  • step 2 rac-2-Methyl-3-oxo-piperidine-1-carboxylic acid benzyl ester
  • step 3 rac-1,2-Dimethyl-3-phenyl-piperidin-3-ylamine
  • step1-3 the title compound was prepared from rac-2-methyl-3-oxo-piperidine-1-carboxylic acid benzyl ester and phenylmagnesium bromide. MS(m/e): 205.2 (M+H + ).
  • step 1 rac-4-(3-Chloro-phenyl)-4-nitro-butyric acid methyl ester
  • step 2 rac-5-(3-Chloro-phenyl)-1-methyl-5-nitro-piperidin-2-one
  • step 3 rac-5-Amino-5-(3-chloro-phenyl)-1-methyl-piperidin-2-one
  • step 4 rac-3-(3-Chloro-phenyl)-1-methyl-piperidin-3-ylamine
  • step 1 rac-4-(4-Methoxy-phenyl)-4-nitro-butyric acid methyl ester
  • the mixture was stirred vigorously for 1 minute at room temperature and the flask was placed in a preheated oil bath at 50 °C and stirred at this temperature overnight.
  • the reaction mixture was cooled to room temperature, and a saturated NH 4 Cl solution and ethyl acetate were added.
  • Aqueous phase was extracted 3 times with ethyl acetate and combined organic phases were washed with brine, and concentrated in vacuo.
  • the crude product was purified with flash column chromatography on silica gel (Eluent: heptane/ethyl acetate 0 to 20 %) to provide 897 mg (90 %) of the title compound as a orange oil.
  • step 2 rac-3-(4-Methoxy-phenyl)-1-methyl-piperidin-3-ylamine
  • step 1 rac-1-Methyl-5-nitro-5-phenyl-piperidin-2-one
  • step 2 rac-3-Fluoro-1-methyl-5-nitro-5-phenyl-piperidin-2-one
  • step 3 rac-5-Amino-3-fluoro-1-methyl-5-phenyl-piperidin-2-one
  • step 4 rac-5-Fluoro-1-methyl-3-phenyl-piperidin-3-ylamine
  • step 1 rac-3-Hydroxy-1-methyl-5-nitro-5-phenyl-piperidin-2-one
  • step 2 rac-3-Methoxymethoxy-1-methyl-5-nitro-5-phenyl-piperidin-2-one
  • step 3 rac-5-Amino-3-methoxymethoxy-1-methyl-5-phenyl-piperidin-2-one
  • step 4 rac-5-Methoxymethoxy-1-methyl-3-phenyl-piperidin-3-ylamine
  • step 1 rac-4-Cyclohexyl-4-nitro-butyric acid methyl ester
  • step 2 rac-5-Cyclohexyl-1-methyl-5-nitro-piperidin-2-one
  • step 3 rac-5-Amine-5-cyclohexyl-1-methyl-piperidin-2-one
  • step 4 rac- 3-Cyclohexyl-1-methyl-piperidin-3-yl-amine
  • step 2 rac-1-Methyl-3-tetrahydro-pyran-4-yl)-piperidin-3-ylamine
  • step 1 rac-3-Isocyanato-3-methyl-piperidine-1-carboxylic acid tert-butyl ester
  • step 2 rac-3-Amino-3-methyl-piperidine-1-carboxylic_acid tert-butyl ester
  • step 3 rac-1,3-Dimethyl-piperidin-3-ylamine dihydrochloride
  • step 1 rac-1-Methyl-3-nitro-2,3,4,5-tetrahydro-1H-[3,4']bipyridinyl-6-one
  • step 2 rac-1-Methyl-3-nitro-2,3,4,5-tetrahydro-1H-[3,4']bipyridinyl-6-thione
  • step 3 rac-1-Methyl-3-nitro-1,2,3,4,5,6-hexahydro-[3-4']bipyridinyl
  • step 4 rac-1-Methyl-1,4,5,6-tetrahydro-2H-[3,4']bipyridinyl-3-ylamine
  • step 1 rac-1-Methyl-3-nitro-2,3,4,5-tetrahydro-1H-[3,3']bipyridinyl-6-one
  • step 2 rac-1-Methyl-1,4,5,6-tetrahydro-2H-[3,3']bipyridinyl-3-ylamine
  • step 1 (3SR,5RS)-3-Methoxy-1-methyl-5-nitro-5-phenyl-piperidin-2-one
  • step 2 (3SR,SRS)-5-Amino-3-methoxy-1-methyl-5-phenyl-piperidin-2-one
  • step 3 (3RS,5SR)-5-Methoxy-1-methyl-3-phenyl-piperidin-3-ylamine
  • step 1 (3SR,5RS)-1,3-Dimethyl-5-nitro-5-phenyl-piperidin-2-one
  • step 2 (3SR,5RS)-5-Amino-1,3-dimethyl-5-phenyl-piperidin-2-one
  • step 4 the title compound was prepared from (3SR,5RS)-1,3-Dimethyl-5-nitro-5-phenyl-piperidin-2-one. MS(m/e): 202.2 (M-NH 2 )
  • step 3 (3RS,5SR)-1,5-Dimethyl-3-phenyl-piperidin-3-ylamine
  • step 2 rac-1,5,5-Trimethyl-3-phenyl-piperidin-3-ylamine
  • step 2 (1-Methyl-6-oxo-3-phenyl-piperidin-3-yl)-carbamic acid tert-butyl ester
  • step 3 (1,6,6-Trimethyl-3-phenyl-piperidin-3-yl)-carbamic acid tert-butyl ester
  • step 4 rac-1,6,6-Trimethyl-3-phenyl-piperidin-3-ylamine
  • step 1 rac-3-(3-Bromo-phenyl)-1-methyl-3-nitro-piperidine
  • step 1-3 the title compound was prepared from 1-Bromo-3-nitromethyl-benzene (CAS:854634-33-6). MS(m/e): 300.3 (M+H).
  • step 2 rac-3-(3-Bromo-phenyl)-1-methyl-piperidin-3-ylamine
  • step 3 the title compound was prepared from rac-3-(3-Bromo-phenyl)-1-methyl-3-nitro-piperidine . MS(m/e): 269.2 (M+H).
  • step 1 rac-4-Nitro-4-phenyl-butyric acid methyl ester
  • step 1 the title compound was prepared from Nitromethyl-benzene (CAS: 622-42-4).
  • step 2 rac-5-Nitro-5-phenyl-piperidin-2-one
  • step 3 rac-5-Amino-5-phenyl-piperidin-2-one
  • step 4 the title compound was prepared from rac-5-Nitro-5-phenyl-piperidin-2-one. MS(m/e): 191.4 (M+H).
  • step 4 rac-3-Phenyl-piperidin-3-ylamine
  • step 4 the title compound was prepared from rac-5-Amino-5-phenyl-piperidin-2-one. MS(m/e): 177.7 (M+H).
  • step 5 rac-2-(3-Amino-3-phenyl-piperidin-1-yl)-2-methyl-propionitrile
  • step 6 rac-1-tert-Butyl-3-phenyl-piperidin-3-ylamine
  • step 1 rac-(4-Methyl-6-phenyl-4-aza-spiro[2.5]oct-6-yl)-carbamic acid tert-butyl ester
  • step 2 rac-4-Methyl-6-phenyl-4-aza-spiro[2.5]oct-6-ylamine hydrochloride
  • step 4 the title compound was prepared from rac-(4-Methyl-6-phenyl-4-aza-spiro[2.5]oct-6-yl)-carbamic acid tert-butyl ester. MS(m/e): 217.4 (M+H).
  • step 1 2-Bromo-4-trifluoromethyl-benzoic acid methyl ester
  • step 2 2-Cyclopropyl-4-trifluoromethyl-benzoic acid methyl ester
  • Example B.2 A mixture of 51 mg (0.191mmol) 2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzoic acid (Example B.2) and 140 ul (1.91mmol) thionylchloride in toluene (0.5ml) was heated in a 80 °C oil bath for 4 hours. The solvent was removed in vacuo to provide the title compound.
  • step 1 2-Ethyl-4,6-bis-trifluoromethyl-benzoic acid
  • step 1 2-Difluoromethoxy-4-trifluoromethyl-benzoic acid methyl ester
  • step 2 2-Difluoromethoxy-4-trifluoromethyl-benzoic acid
  • step 3 the title compound was prepared from 2-difluoromethoxy-4-trifluoromethyl-benzoic acid methyl ester. MS(m/e): 254.9 (M-H)
  • step 1 2-Pyrrolidin-1-yl-4-trifluoromethyl-benzoic acid methyl ester
  • step 2 2-Pyrrolidin-1-yl-4-trifluoromethyl-benzoic acid
  • step 3 the title compound was prepared from 2-pyrrolidin-1-yl-4-trifluoromethyl-benzoic acid methyl ester. MS(m/e): 258.0 (M-H).
  • step 1 2-Iodo-4-trifluoromethyl-benzoic acid methyl ester
  • step 1 the title compound was prepared from 2-iodo-4-trifluoromethyl-benzoic acid (CAS: 54507-44-7).
  • step 2 2-Cyclohexyl-4-trifluoromethyl-benzoic acid methyl ester
  • step 3 2-Cyclohexyl-4-trifluoromethyl-benzoic acid
  • step 3 the title compound was prepared from 2-cyclohexyl-4-trifluoromethyl-benzoic acid methyl ester. MS(m/e): 271.2 (M-H)
  • step 2 2-Methoxy-6-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-benzonitrile.
  • step 3 2-Methoxy-6-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-benzoic acid
  • step 1 2-(2-Methoxy-4-trifluoromethyl-phenyl)-4,4-dimethyl-4,5-dihydro-oxazole
  • step 2 2-(2-Methoxy-3-methyl-4-trifluoromethyl-phenyl)-4,4-dimethyl-4,5-dihydro-oxazole
  • step 3 2-(2-Ethyl-3-methyl-4-trifluoromethyl-phenyl)-4,4-dimethyl-4,5-dihydro-oxazole
  • step 4 2-(2-Ethyl-3-methyl-4-trifluoromethyl-phenyl)-3,4,4-trimethyl-4,5-dihydro-oxazol-3-ium iodide
  • step1 (3-Hydroxy-1-methyl-propyl)-methyl-carbamic acid tert-butyl ester
  • step2 (3-Bromo-1-methyl-propyl)-methyl-carbamic acid tert-butyl ester
  • step3 Methyl-(1-methyl-4-nitro-4-phenyl-butyl)-carbamic acid tert-butyl ester
  • step 4 the title compound was prepared from Methyl-(1-methyl-4-nitro-4-phenyl-butyl)-carbamic acid tert-butyl ester. MS(m/e): 223.3 (M+H).
  • step7 N-(1,6-Dimethyl-3-phenyl-piperidin-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide
  • step 1 rac-3-Amino-3-phenyl-piperidine-1-carboxylic acid benzyl ester
  • step 2 rac- 3-(2-Methoxy-4,6-bis-trifluoromethyl-benzoylamino)-3-phenyl-piperidine-1-carboxylic acid benzyl ester
  • step 3 rac-2-Methoxy-N-(3-phenyl-piperidin-3-yl)-4,6-bis-trifluoromethyl-benzamide
  • Example No. Structure Systematic Name Starting materials MW found (MH + ) 39 rac-2-Difluoromethoxy-N-(1-methyl-3-phenyl-piperidin-3-yl)-4-trifluoromethyl-benzamide rac-1-Methyl-3-phenyl-piperidin-3-ylamine (Example A.1) and 2-Difluoromethoxy-4-trifluoromethyl-benzoic acid (Example B.8) 429.2 40 rac-2-Chloro-N-(1-methyl-3-phenyl-piperidin-3-yl)-6-trifluoromethyl-nicotinamide hydrochloride rac-1-Methyl-3-phenyl-piperidin-3-ylamine (Example A.1) and 2-chloro-6-(trifuoromethyl)nicotinic acid (commercial) 398.1 41 rac-2-
  • step 1 rac-3-(2-Methoxy-6-methylsulfanyl-4-trifluoromethyl-benzoylaminol-3-phenylpiperidine-1-carboxylic acid benzyl ester
  • step 2 rac-2-Methoxy-6-methylsulfanyl-N-(3-phenyl-peridin-3-yl)-4-trifluoromethyl-benzamide hydrochloride
  • step 1 rac-2-Methoxy-(5-methoxymethoxy-1-methyl-3-phenyl-piperidin-3-yl)-6-methylsulfanyl-4-trifluoromethyl-benzamide
  • step 2 rac-N-(5-Hydroxy-1-methyl-3-phenyl-piperidin-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide
  • the examples 56-57 have been prepared by separation of the racemic material by chiral HPLC followed by formation of the hydrochloride salt with HCl/Methanol: Expl. No. Structure Systematic Name Starting racemic material Retention time (min.) * MW found (MH + ) 56 2-Cyclopropyl-N-((S)-1-methyl-3-phenyl-piperidin-3-yl)-4-trifluoromethyl-benzamide hydrochloride rac-2-Cyclopropyl-N-(1-methyl-3-phenyl-piperidin-3-yl)-4-trifluoromethyl-benzamide (Example 13) 5.6 403.3 57 2-Cyclopropyl-N-((R)-1-methyl-3-phenyl-piperidin-3-yl)-4-trifluoromethyl-benzamide hydrochloride rac-2-Cyclopropyl-N-(1-methyl-3-phenyl-piperidin-3-yl)-4-trifluoromethyl-benzamide
  • the examples 61-62 have been prepared by separation of the racemic material by chiral HPLC: Expl. No. Structure Systematic Name Starting racemic material Retention time (min.) * MW found (MH + ) 61 2-Methoxy-6-methylsulfanyl-N-((S) or (R)-3-phenyl-piperidin-3-yl)-4-trifluoromethyl-benzamide rac-2-Methoxy-6-methylsulfanyl-N-(3-phenyl-piperidin-3-yl)-4-trifluoromethyl-benzamide (Example 50) 11.0 425.1 62 2-Methoxy-6-methylsulfanyl-N-((R) or (S)-3-phenyl-piperidin-3-yl)-4-trifluoromethyl-benzamide rac-2-Methoxy-6-methylsulfanyl-N-(3-phenyl-piperidin-3-yl)-4-trifluoromethyl-benzamide (Example 50) 1
  • step 1 rac-2-Methoxy-N-(1-methyl-5-oxo-3-phenyl-piperidin-3-yl)-6-methylsulfanyl-4-trifluoromethyl-benzamide
  • step 2 N-((3RS,5RS)-5-Hydroxy-1-methyl-3-phenyl-piperidin-3-yl)-2-methoxy-6 methylsulfanyl-4-trifluoromethyl-benzamide
  • the examples 106-128 have been prepared by separation of the racemic material by chiral HPLC: Expl. No. Structure Systematic Name Starting racemic material Column type Retention time (min.) * MW found (MH + ) 106 N-((3S,5R) or (3R,5S)-5-Hydroxy-1-methyl-3-phenyl-piperidin-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide hydrochloride rac-N-(5-Hydroxy-1-methyl-3-phenyl-piperidin-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide (Example 51) A 6.9 455.2 107 N-((3R,5S) or (3S,5R)-5-Hydroxy-1-methyl-3-phenyl-piperidin-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benz
  • the compounds of formula I and their pharmaceutically usable addition salts possess valuable pharmacological properties. Specifically, it has been found that the compounds of the present invention are good inhibitors of the glycine transporter I (GlyT-1).
  • DMEM complete medium Nutrient mixture F-12 (Gibco Life-technologies), fetal bovine serum (FBS) 5 %, (Gibco life technologies), Penicillin/Streptomycin % (Gibco life technologies), Hygromycin 0.6 mg/ml (Gibco life technologies), Glutamine 1 mM Gibco life technologies)
  • Flp-inTM-CHO (Invitrogen Cat n° R758-07)cells stably transfected with mGlyTlb cDNA.
  • mammalian cells (Flp-inTM-CHO), transfected with mGlyT-1b cDNA, were plated at the density of 40,000 cells/well in complete F-12 medium, without hygromycin in 96-well culture plates.
  • the medium was aspirated and the cells were washed twice with uptake buffer (UB).
  • the cells were then incubated for 20 min at 22 °C with either (i) no potential competitor, (ii) 10 mM non-radioactive glycine , (iii) a concentration of a potential inhibitor.
  • a range of concentrations of the potential inhibitor was used to generate data for calculating the concentration of inhibitor resulting in 50 % of the effect (e.g.
  • IC 50 the concentration of the competitor inhibiting glycine uptake of 50 %).
  • a solution was then immediately added containing [ 3 H]-glycine 60 nM (11-16 Ci/mmol) and 25 ⁇ M non-radioactive glycine.
  • the plates were incubated with gentle shaking and the reaction was stopped by aspiration of the mixture and washing (three times) with ice-cold UB.
  • the cells were lysed with scintillation liquid, shaken 3 hours and the radioactivity in the cells was counted using a scintillation counter.
  • the compounds described in examples 1 -60 have an IC 50 data ⁇ 1.0 ⁇ M.
  • the preferred IC 50 data ( ⁇ 0.2 ⁇ M) for compounds 1 -128 is be provided in table 1.
  • Table 1 Example IC 50 data ( ⁇ M)
  • Example IC 50 data ( ⁇ M) 4 0.0264 77 0.0881 5 0.1074 80 0.1759 7 0.0854 82 0.0253 11 0.0202 83 0.03 13 0.013 84 0.0173 16 0.1379 85 0.0313 18 0.0244 86 0.0715 19 0.0672 87 0.0396 25 0.1256 88 0.1457 26 0.0593 89 0.107 27 0.0262 91 0.1132 28 0.0277 93 0.0479 36 0.0839 94 0.0596 37 0.1817 95 0.0515 38 0.0101 96 0.0682 39 0.1843 97 0.1851 45 0.0245 98 0.0622 46 0.1693 99 0.0366 47 0.1811 103 0.0773 48 0.1973 104 0.1734 51 0.0582 105 0.02
  • the compounds of formula I and the pharmaceutically acceptable salts of the compounds of formula I can be used as medicaments, e.g. in the form of pharmaceutical preparations.
  • the pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragées, hard and soft gelatine capsules, solutions, emulsions or suspensions.
  • the administration can, however, also be effected rectally, e.g. in the form of suppositories, parenterally, e.g. in the form of injection solutions.
  • the compounds of formula I can be processed with pharmaceutically inert, inorganic or organic carriers for the production of pharmaceutical preparations.
  • Lactose, corn starch or derivatives thereof, talc, stearic acids or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragées and hard gelatine capsules.
  • Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. Depending on the nature of the active substance no carriers are however usually required in the case of soft gelatine capsules.
  • Suitable carriers for the production of solutions and syrups are, for example, water, polyols, glycerol, vegetable oil and the like.
  • Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.
  • the pharmaceutical preparations can, moreover, contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
  • Medicaments containing a compound of formula I or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier are also an object of the present invention, as is a process for their production, which comprises bringing one or more compounds of formula I and/or pharmaceutically acceptable acid addition salts and, if desired, one or more other therapeutically valuable substances into a galenical administration form together with one or more therapeutically inert carriers.
  • the most preferred indications in accordance with the present invention are those, which include disorders of the central nervous system, for example the treatment or prevention of schizophrenia, cognitive impairment and Alzheimer's disease.
  • the dosage can vary within wide limits and will, of course, have to be adjusted to the individual requirements in each particular case.
  • the dosage for adults can vary from about 0.01 mg to about 1000 mg per day of a compound of general formula I or of the corresponding amount of a pharmaceutically acceptable salt thereof.
  • the daily dosage may be administered as single dose or in divided doses and, in addition, the upper limit can also be exceeded when this is found to be indicated.
  • Tablet Formulation (Wet Granulation) Item Ingredients mg/tablet 5 mg 25 mg 100 mg 500 mg 1.
  • Compound of formula I 5 25 100 500 2.
  • Lactose Anhydrous DTG 125 105 30 150 3.
  • Sta-Rx 1500 6 6 6 30 4.
  • Microcrystalline Cellulose 30 30 30 150 5.

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Claims (22)

  1. Composé de formule générale
    Figure imgb0287
     dans laquelle :
    R1 est un hydrogène, un alkyle en C1-C7, CD3, -(CH2)n-CHO, -(CH2)n-O-(alkyle en C1-C7), -(CH2)n-OH, -(CH2)n-(cycloalkyle en C3-C7), le cycloalkyle étant un cycle saturé ou partiellement saturé, ou est un hétérocycloalkyle choisi dans le groupe constitué par pipérazinyle, pyrrolidinyle, oxétanyle, morpholinyle, pipéridinyle ou tétrahydropyranyle ;
    R2 est un hydrogène, un halogène, un hydroxy, un alkyle en C1-C7, un dialkyle en C1-C7, -OCH2-O-(alkyle en C1-C7), ou un alcoxy en C1-C7; ou le cycle pipéridine forme avec R2 un cycle spiro choisi parmi 4-azaspiro[2.5]oct-6-yle ;
    Ar est un aryle ou un hétéroaryle, qui sont éventuellement substitués par 1, 2 ou 3 substituants choisis parmi halogène, alkyle en C1-C7, alkyle en C1-C7 substitué par halogène, alcoxy en C1-C7 substitué par halogène, cycloalkyle en C3-C7, le cycloalkyle étant un cycle saturé ou partiellement saturé, alcoxy en C1-C7, S-alkyle en C1-C7, hétéroaryle, hétérocycloalkyle choisi dans le groupe constitué par pipérazinyle, pyrrolidinyle, oxétanyle, morpholinyle, pipéridinyle ou tétrahydropyranyle, ou par phényle éventuellement substitué par R', et
    R' est un halogène, un alkyle en C1-C7, un alcoxy en C1-C7 ou un alcoxy en C1-C7 substitué par halogène, ou est un hétéroaryle ;
    R est un alkyle en C1-C7, un cycloalkyle en C3-C7, le cycloalkyle étant un cycle saturé ou partiellement saturé, un hétérocycloalkyle choisi dans le groupe constitué par pipérazinyle, pyrrolidinyle, oxétanyle, morpholinyle, pipéridinyle ou tétrahydropyranyle, ou est un aryle ou un hétéroaryle, l'aryle et l'hétéroaryle étant éventuellement substitués par 1 ou 2 R' ;
    n est 0, 1, 2 ou 3;
    ou un sel d'addition d'acide pharmaceutiquement acceptable, un mélange racémique, ou son énantiomère et/ou isomère optique correspondant, de celui-ci.
  2. Composé de formule 1 selon la revendication 1, dans lequel R1 est un alkyle en C1-C7.
  3. Composé de formule 1 selon la revendication 2, dans lequel Ar et R sont tous les deux un phényle.
  4. Composé de formule 1 selon la revendication 3, dans lequel le groupe phényle représenté par Ar est substitué par au moins 2 groupes CF3.
  5. Composé de formule 1 selon la revendication 4, le composé étant :
    le rac-2-fluoro-N-(1-méthyl-3-phénylpipéridin-3-yl)-4,6-bis-trifluorométhylbenzamide
    le rac-2-méthoxy-N-(1-méthyl-3-phénylpipéridin-3-yl)-4,6-bis-trifluorométhylbenzamide
    le rac-2-éthyl-N-(1-méthyl-3-phénylpipéridin-3 -yl)-4,6-bis-trifluorométhylbenzamide le rac-N-[3-(4-fluorophényl)-1-méthylpipéridin-3-yl]-2-méthoxy-4,6-bis-trifluorométhylbenzamide ou
    le 2-méthoxy-N-((R)-1-méthyl-3-phénylpipéridin-3-yl)-4,6-bis-trifluorométhylbenzamide .
  6. Composé de formule 1 selon la revendication 3, dans lequel le groupe phényle représenté par Ar est substitué par au moins un groupe CF3.
  7. Composé de formule 1 selon la revendication 6, le composé étant :
    le rac-2-éthyl-N-(1-méthyl-3-phénylpipéridin-3-yl)-4-trifluorométhylbenzamide le rac-2-bromo-6-méthoxy-N-(1-méthyl-3-phënylpipéridin-3-yl)-4-trifluorométhylbenzamide
    le rac-N-(1,2-diméthyl-3-phénylpipéridin-3-yl)-2-méthoxy-6-méthylsulfanyl-4-trifluorométhylbenzamide
    le rac-2-cyclopropyl-N-(1-méthyl-3-phénylpipéridin-3-yl)-4-trifluorométhylbenzamide
    le rac-2-méthoxy-N-(1-méthyl-3-phénylpipéridin-3-yl)-6-méthylsulfanyl-4-trifluorométhylbenzamide
    le rac-N-(1-méthyl-3-phénylpipéridin-3-yl)-2-méthylsulfanyl-4-trifluorométhylbenzamide
    le rac-N-[3-(4-fluorophényl)-1-méthylpipéridin-3-yl]-2-méthoxy-6-méthylsulfanyl-4-trifluorométhylbenzamide
    le rac-N-[3-(4-chlorophényl)-1-méthylpipéridin-3-yl]-2-méthoxy-6-méthylsulfanyl-4-trifluorométhylbenzamide
    le 2-méthoxy-N-((S)-1-méthyl-3-phénylpipéridin-3-yl)-6-méthylsulfanyl-4-trifluorométhylbenzamide
    le 2-méthoxy-N-((R)-1-méthyl-3-phénylpipéridin-3-yl)-6-méthylsulfanyl-4-trifluorométhylbenzamide
    le rac-2-difluorométhoxy-N-(1-méthyl-3-phénylpipéridin-3-yl)-4-trifluorométhylbenzamide
    la rac-N-[3-(3-chlorophényl)-1-méthylpipéridin-3-yl]-2-méthoxy-6-méthylsulfanyl-4-trifluorométhylbenzamide
    le rac-2-méthoxy-N-[3-(4-méthoxy-phényl)-1-méthylpipéridin-3-yl]-6-méthylsulfanyl-4-trifluorométhylbenzamide
    le rac-N-(5-fluoro-1-méthyl-3-phénylpipéridin-3-yl)-2-méthoxy-6-méthylsulfanyl-4-trifluorométhylbenzamide
    le rac-N-(1-isopropyl-3-phénylpipéridin-3-yl)-2-méthoxy-6-méthylsulfanyl-4-trifluorométhylbenzamide
    le 2-cyclopropyl-N-((S)-1-méthyl-3-phénylpipéridin-3-yl)-4-trifluorométhylbenzamide
    le 2-cyclopropyl-N-((R)-1-méthyl-3-phénylpipéridin-3-yl)-4-trifluorométhylbenzamide
    le rac-2-cyclobutyl-N-(1-méthyl-3-phénylpipéridin-3-yl)-4-trifluorométhylbenzamide le rac-N-[3-(2,4-difluorophényl)-1-méthylpipéridin-3-yl]-2-méthoxy-6-méthylsulfanyl-4-trifluorométhylbenzamide
    le rac-N-[3-(2-fluorophényl)-1-méthylpipéridin-3-yl]-2-méthoxy-6-méthylsulfanyl-4-trifluorométhylbenzamide
    le rac-N-[3-(2,5-difluorophényl)-1-méthylpipéridin-3-yl]-2-méthoxy-6-méthylsulfanyl-4-trifluorométhylbenzamide
    le rac-2-isopropyl-N-(1-méthyl-3-phénylpipéridin-3-yl)-4-trifluorométhylbenzamide le rac-2-méthoxy-6-méthylsulfanyl-N-(l -méthyl-1,4,5, 6-tétrahydro-2H-[3,4']bipyridinyl-3-yl)-4-trifluorométhylbenzamide
    le rac-2-éthyl-N-(1-méthyl-1,4,5,6-tétrahydro-2H-[3,4']bipyridinyl-3-yl)-4-trifluorométhylbenzamide
    le rac-2-méthoxy-6-méthylsulfanyl-N-(1-méthyl-1,4,5,6-tétrahydro-2H-[3,3']bipyridinyl-3-yl)-4-trifluorométhylbenzamide
    le chlorhydrate du rac-2-éthyl-N-(1-méthyl-1,4,5,6-tétrahydro-2H-[3,3']bipyridinyl-3-yl)-4-trifluorométhylbenzamide
    le 2-méthoxy-N-((3RS,5SR)-5-méthoxy-1-méthyl-3-phénylpipéridin-3-yl)-6-méthylsulfanyl-4-trifluorométhylbenzamide
    le 2-cyclopropyl-N-((3RS,5SR)-5-méthoxy-1-méthyl-3-phénylpipéridin-3-yl)-4-trifluorométhylbenzamide
    le 2-éthyl-N-((3RS,5SR)-5-méthoxy-1-méthyl-3-phénylpipéridin-3-yl)-4-trifluorométhylbenzamide
    le rac-2, 6-diméthoxy-N-(1-méthyl-3-phénylpipéridin-3-yl)-4-trifluorométhylbenzamide
    le 2-cyclopropyl-N-((3RS, 5SR)-1,5-diméthyl-3-phénylpipéridin-3-yl)-4-trifluorométhylbenzamide
    le rac-2-cyclopropyl-4-trifluorométhyl-N-(1,5,5-triméthyl-3-phénylpipéridin-3-yl)benzamide
    le rac-2-méthoxy-6-méthylsulfanyl-4-trifluorométhyl-N-(1,6,6-triméthyl-3-phénylpipéridin-3-yl)benzamide
    le N-((3RS,5SR)-1,5-diméthyl-3-phénylpipéridin-3-yl)-2-méthoxy-6-méthylsulfanyl-4-trifluorométhylbenzamide
    le 2-méthoxy-N-((3RS,5SR)-5-méthoxyméthoxy-1-méthyl-3-phénylpipéridin-3-yl)-6-méthylsulfanyl-4-trifluorométhylbenzamide
    le rac-N-[3-(3-bromophényl)-1-méthylpipéridin-3-yl]-2-méthoxy-6-méthylsulfanyl-4-trifluorométhylbenzamide
    le rac-N-[3-(2-chloro-4-fluorophényl)-1-méthylpipéridin-3-yl]-2-méthoxy-6-méthylsulfanyl-4-trifluorométhylbenzamide
    le rac-2-méthoxy-6-méthylsulfanyl-N-[1-méthyl-3-(3-trifluorométhylphényl)-pipéridin-3-yl]-4-trifluorométhylbenzamide
    le rac-2-méthoxy-N-[3-(3-méthoxy-phényl)-1-méthylpipéridin-3-yl]-6-méthylsulfanyl-4-trifluorométhylbenzamide
    le rac-N-[3-(3-fluorophényl)-1-méthylpipéridin-3-yl]-2-mëthoxy-6-méthylsulfanyl-4-trifluorométhylbenzamide
    le rac-N-[3-(3-chloro-4-fluorophényl)-1-méthylpipéridin-3-yl]-2-méthoxy-6-méthylsulfanyl-4-trifluorométhylbenzamide
    le rac-N-[3-(3,4-difluorophényl)-1-méthylpipéridin-3-yl]-2-méthoxy-6-méthylsulfanyl-4-trifluorométhylbenzamide
    le rac-2-méthoxy-6-méthylsulfanyl-N-(1-méthyl-3-m-tolylpipéridin-3-yl)-4-trifluorométhylbenzamide
    le rac-N-[3-(4-fluoro-3-méthylphényl)-1-méthylpipéridin-3-yl]-2-méthoxy-6-méthylsulfanyl-4-trifluorométhylbenzamide
    le rac-N-[3-(3,5-difluorophényl)-1-méthylpipéridin-3-yl]-2-méthoxy-6-méthylsulfanyl-4-trifluorométhylbenzamide
    le rac-2-méthoxy-6-méthylsulfanyl-4-trifluorométhyl-N-(1,5,5-triméthyl-3-phénylpipéridin-3-yl)benzamide
    le rac-2-éthyl-3-méthyl-N-(1-méthyl-3-phénylpipéridin-3-yl)-4-trifluorométhylbenzamide
    le rac-N-(1-tert-butyl-3-phénylpipéridin-3-yl)-2-méthoxy-6-méthylsulfanyl-4-trifluorométhylbenzamide
    le rac-2-méthoxy-N-(4-méthyl-6-phényl-4-azaspiro[2.5]oct-6-yl)-6-méthylsulfanyl-4-trifluorométhylbenzamide
    le N-((3R,5S) ou (3S,5R)-5-hydroxy-1-méthyl-3-phénylpipéridin-3-yl)-2-méthoxy-6-méthylsulfanyl-4-trifluorométhylbenzamide
    le 2-méthoxy-N-((3R,5S) ou (3S,5R)-5-méthoxy-1-méthyl-3-phénylpipéridin-3-yl)-6-méthylsulfanyl-4-trifluorométhylbenzamide
    le 2-méthoxy-N-((3S,5R) ou (3R,5S)-5-méthoxy-1-méthyl-3-phénylpipéridin-3-yl)-6-méthylsulfanyl-4-trifluorométhylbenzamide
    le N-[(R ou S)-3-(2-fluorophényl)-1-méthylpipéridin-3-yl]-2-méthoxy-6-méthylsulfanyl-4-trifluorométhylbenzamide
    le N-[(R ou S)-3-(2,5-difluorophényl)-1-méthylpipéridin-3-yl]-2-méthoxy-6-méthylsulfanyl-4-trifluorométhylbenzamide
    le 2-éthyl-N-((R ou S)-1-méthyl-3-phénylpipéridin-3-yl)-4-trifluorométhylbenzamide le 2-méthoxy-6-méthylsulfanyl-4-trifluorométhyl-N-((S ou R)-1,5,5-triméthyl-3-phénylpipéridin-3-yl)benzamide
    le N-((3S,6S) ou (3R,6R)-1,6-diméthyl-3-phénylpipéridin-3-yl)-2-méthoxy-6-méthylsulfanyl-4-trifluorométhylbenzamide
    le N-((3R,6R) ou (3S,6S)-1,6-diméthyl-3-phénylpipéridin-3-yl)-2-méthoxy-6-méthylsulfanyl-4-trifluorométhylbenzamide
    le N-((3R,6S) ou (3S,6R)-1,6-diméthyl-3-phénylpipéridin-3-yl)-2-méthoxy-6-méthylsulfanyl-4-trifluorométhylbenzamide
    le N-((3S,5R) ou (3R,5S)-1,5-diméthyl-3-phénylpipéridin-3-yl)-2-méthoxy-6-méthylsulfanyl-4-trifluorométhylbenzamide
    le N-((3R,5S) ou (3S,5R)-1,5-diméthyl-3-phénylpipéridin-3-yl)-2-éthyl-4-trifluorométhylbenzamide
    le 2-éthyl-N-((3R,5S) ou (3S,5R)-5-méthoxy-1-méthyl-3-phénylpipéridin-3-yl)-4-trifluorométhylbenzamide
    le 2-cyclopropyl-N-((3R,5S) ou (3S,5R)-5-méthoxy-1-méthyl-3-phénylpipéridin-3-yl)-4-trifluorométhylbenzamide ou
    le 2, 6-diméthoxy-N-(R ou S)-1-méthyl-3-phénylpipéridin-3-yl)-4-trifluorométhylbenzamide.
  8. Composé de formule 1 selon la revendication 1, dans lequel R1 est un cycloalkyle en C3-C7, le cycloalkyle étant un cycle saturé ou partiellement saturé, ou un hétérocycloalkyle choisi dans le groupe constitué par pipérazinyle, pyrrolidinyle, oxétanyle, morpholinyle, pipéridinyle ou tétrahydropyranyle, et Ar et R sont tous les deux un phényle.
  9. Composé des formule 1 selon la revendication 8, le composé étant :
    le rac-N-(1-cyclopentyl-3-phénylpipéridin-3-yl)-2-méthoxy-4,6-bis-trifluorométhylbenzamide
    le rac-N-(1-cyclopropylméthyl-3-phénylpipéridin-3-yl)-2-méthoxy-4,6-bis-trifluorométhylbenzamide ou
    le rac-2-méthoxy-N-[3-phényl-1-(tétrahydropyran-4-yl)-pipéridin-3-yl]-4,6-bis-trifluorométhylbenzamide.
  10. Composé de formule 1 selon la revendication 1, dans lequel R1 est un alkyle en C1-C7, Ar est un phényle et R est un hétéroaryle.
  11. Composé de formule 1 selon la revendication 10, le composé étant :
    le rac-N-(5-fluoro-1'-méthyl-1',4',5',6'-tétrahydro-2'H-[2,3']bipyridinyl-3'-yl)-2-méthoxy-6-méthylsulfanyl-4-trifluorométhylbenzamide
    le rac-2-méthoxy-6-méthylsulfanyl-N-(1-méthyl-1,4,5,6-tétrahydro-2H-[3,4']bipyridinyl-3-yl)-4-trifluorométhylbenzamide
    le chlorhydrate du rac-2-éthyl-N-(1-méthyl-1,4,5,6-tétrahydro-2H-[3,4']bipyridinyl-3-yl)-4-trifluorométhylbenzamide
    le rac-2-méthoxy-6-méthylsulfanyl-N-(1-méthyl-1,4,5,6-tëtrahydro-2H-[3,3']bipyridinyl-3-yl)-4-trifluorométhylbenzamide ou
    le rac-2-éthyl-N-(1-méthyl-1,4,5,6-tétrahydro-2H-[3,3']bipyridinyl-3-yl)-4-trifluorométhylbenzamide.
  12. Composé de formule I selon la revendication 1, dans lequel R1 est un hydrogène et Ar et R sont un phényle.
  13. Composé de formule I selon la revendication 12, le composé étant le rac-2-cyclopropyl-N-(3-phénylpipéridin-3-yl)-4-trifluorométhylbenzamide.
  14. Composé de formule I selon la revendication 1, dans lequel R2 est un hydroxy.
  15. Composé de formule I selon la revendication 14, le composé étant :
    le rac-N-(5-hydroxy-1-méthyl-3-phénylpipéridin-3-yl)-2-méthoxy-6-méthylsulfanyl-4-trifluorométhylbenzamide ou
    le N-((3R,5S) ou (3S,5R)-5-hydroxy-1-méthyl-3-phénylpipéridin-3-yl)-2-méthoxy-6-méthylsulfanyl-4-trifluorométhylbenzamide.
  16. Composé de formule I selon la revendication 3, dans lequel R2 est un halogène.
  17. Composé de formule I selon la revendication 16, le composé étant le rac-N-(5-fluoro-1-méthyl-3-phénylpipéridin-3-yl)-2-méthoxy-6-méthylsulfanyl-4-trifluorométhylbenzamide.
  18. Composé de formule I selon la revendication 1, dans lequel R1 est CD3.
  19. Composé de formule I selon la revendication 18, le composé étant le chlorhydrate du [2H-méthyl]-2-méthoxy-N-(R) ou (S)-1-méthyl-3-phénylpipéridin-3-yl)-6-méthylsulfanyl-4-trifluorométhylbenzamide.
  20. Procédé de préparation d'un composé de formule I et de son sel pharmaceutiquement acceptable, ce procédé comprenant :
    a) la réaction d'un composé de formule
    Figure imgb0288
     avec un composé de formule
    Figure imgb0289
     en présence d'un agent d'activation choisi parmi le HATU (hexafluorophosphate de o-(7-azabenzotriazol-1-yl)-1,1,3,3-tétraméthyluronium) ou le chlorure de thionyle donnant un composé de formule
    Figure imgb0290
     où les substituants sont tels que définis dans la revendication 1, ou
    b) la réaction d'un composé de formule
    Figure imgb0291
     avec un composé de formule
    R1X
    en présence d'une base choisie parmi la N-éthyldiisopropylamine, donnant un composé de formule
    Figure imgb0292
     où X est un halogène et les autres substituants sont tels que définis dans la revendication 1, ou
    c) la réaction d'un composé de formule
    Figure imgb0293
     avec un réactif carbonyle de formule R4-C(O)-R5,
    en présence d'un agent réducteur choisi parmi le cyanoborohydrure de sodium, donnant un composé de formule
    Figure imgb0294
     où les substituants sont tels que définis dans la revendication 1 et R4 et R5 sont des groupes alkyle en C1-C7 ou forment ensemble, avec l'atome de carbone auquel ils sont liés, un cycloalkyle en C3-C7 ou un groupe hétérocycloalkyle choisi dans le groupe constitué par pipérazinyle, pyrrolidinyle, oxétanyle, morpholinyle, pipéridinyle ou tétrahydropyranyle, et
    si désiré, la conversion des composés obtenus en sels d'addition d'acide pharmaceutiquement acceptables.
  21. Médicament contenant un ou plusieurs composés selon l'une quelconque des revendications 1 à 19 et des excipients pharmaceutiquement acceptables pour le traitement de maladies basées sur l'inhibiteur de la capture de la glycine, les maladies étant des psychoses, la douleur, le dysfonctionnement de la mémoire et de l'apprentissage, le déficit de l'attention, la schizophrénie, des troubles de démence ou la maladie d'Alzheimer.
  22. Utilisation d'un composé selon l'une quelconque des revendications 1 à 19 pour la fabrication de médicaments destinés au traitement de psychoses, de la douleur, du dysfonctionnement de la mémoire et de l'apprentissage, du déficit de l'attention, de la schizophrénie, des troubles de démence ou de la maladie d'Alzheimer.
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